Infectious diseases are the third leading cause of death in developed countries and the second leading cause of death worldwide (see, e.g., World Health Organization (WHO) Geneva, World Health Report (2002); Nathan, Nature (2004) 431:899). The efficacy of many antibacterial drugs has been compromised by the emergence of drug resistant, pathogenic bacteria (see, e.g., National Nosocomial Infections Surveillance (NNIS) System, Am. J. Infect. Control (2004) 32:470). The Infectious Disease Society of America has recently outlined the deadly implications of a growing number of drug-resistant pathogens (see, e.g., Boucher et al., J. Clin. Infect. Dis. (2009) 48:1). Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE), and penicillin-resistant Streptococcus epidermis are especially worrisome in clinical settings. Unfortunately, the prevalence of multidrug-resistant bacteria has made antibiotics of last resort, like vancomycin, the first-line of therapy. The capacity of bacteria to routinely develop resistance to virtually any antibacterial agent necessitates a continuous search for new drugs. There is much evidence in the literature that natural products derived from microorganisms will continue to be a source of novel antibacterial drugs (see, e.g., Clardy, Nat. Biotechnol. (2006) 24:1541). Although natural products often have chemical properties that are incompatible with chemotherapy, it is possible to use medicinal chemistry as a means to enhance their biological activity and/or pharmacological properties (see, e.g., von Nussbaum et al., Angew. Chem. Int. Ed. (2006) 45:5072).
A recent case where medicinal chemistry was used to improve the activity of a natural product was that of the enopeptins (see, e.g., Hinzen et al., Chem Med Chem (2006) 1:689; U.S. 20050107288). The parent compounds were isolated from the soil-dwelling bacterium Streptomyces sp. RK-1051 and are defined by a 16-membered peptidolactone consisting of five L-amino acids to which a lipophilic polyene side chain is appended (see, e.g., Osada et al., J. Antibiot. (1991) 44:1463). A group of closely related compounds, called A54556 A and B, were isolated from Streptomyces hawaiienesis by a research group at Eli Lilly (U.S. Pat. No. 4,492,650). The enopeptins attracted attention because of their potent activity against drug-resistant bacterial pathogens, including MRSA and VRE (see, e.g., Brötz-Oesterhelt et al., Nat. Med. (2005) 11:1082). The apparent lack of cross-resistance for all antibacterial agents on the market or those in clinical development has been ascribed to a peculiar mechanism of action. The enopeptin antibiotics inhibit cell division and cause cell death by binding and deregulating the activity of the casein lytic protease (ClpP) (see, e.g., Brötz-Oesterhelt, supra). Under normal conditions, this fourteen-subunit protease selectively degrades proteins through a physical and functional association with accessory ATPases that recognize and unfold its substrates (see, e.g., Maurizi et al., Biochemistry (1999) 37:7778; Singh et al., Proc. Natl. Acad. Sci., USA. (2000) 97:8898; Baker et al., Trends Biochem. Sci. (2006) 31:647; Hsiung et al., FEBS Lett. (2007) 581: 3749). In the presence of the enopeptins, ClpP indiscriminately degrades folded cytoplasmic proteins, which ultimately causes cell death (see, e.g., Brötz-Oesterhelt, supra). Recent structural studies indicate that the enopeptins bind the ClpP core structure and cause it to undergo a conformational change that exposes the enzymatic active sites of its subunits (see, e.g., Lee et al., Nature Structural Biology (2010) 17:471-479).
Although the enopeptin natural products have remarkable antibacterial activity in vitro, their chemical lability and poor solubility limit their efficacy in vivo (see, e.g., Hinzen et al., Chem Med Chem (2006) 1:689). Therefore, this continues to be a need for the development and study of new and improved enopeptin compounds.